The tongue is an important muscular organ and carries out crucial physiological functions. Despite the important functions of the tongue in our daily life, we know very little about the regulatory mechanism of mammalian tongue muscle development. The long term goal of this project is to understand the molecular and cellular mechanisms that control tissue-tissue interactions during tongue myogenesis. Specifically, our preliminary studies show that cranial neural crest (CNC) cells contribute to the interstitial connective tissue, which ultimately compartmentalizes both intrinsic and extrinsic tongue muscles and serves as their attachments. Occipital somite-derived cells migrate into tongue primordium and give rise to muscle cells in the tongue. The intimate relationship between CNC- and mesoderm-derived cells suggests that tissue-tissue interaction may play an important role in regulating tongue development. Transforming growth factor- (TGF- ) and its signaling mediator Smad are expressed in both CNC- and mesoderm-derived cells in the tongue. Significantly, disruption of TGF- signaling in either CNC or mesoderm-derived cells does not adversely affect cell migration into the tongue primordium, indicating that TGF- signaling is specifically required locally during tongue morphogenesis. We discovered that mutation of Tgfbr in CNC cells results in a defect in tongue muscle patterning and microglossia, whereas loss of Tgfbr in mesoderm-derived cells results in a myogenic differentiation defect with 100% phenotype penetrance. Taking advantage of our neural crest- or mesoderm- specific Tgfbr2 mutant animal models, we designed studies to test the hypothesis that TGF- signaling controls the fate of CNC as well as mesoderm-derived cells and regulates tissue-tissue interaction during tongue development. Ultimately, this study will provide a better understanding of how the TGF- signaling cascade regulates the fate of the CNC- and mesoderm derived cells during normal craniofacial development and how signaling pathway disruption can lead to craniofacial malformations. This study will have a broad impact on our understanding of the regulatory mechanism of skeletal muscle development and regeneration. PUBLIC HEALTH RELEVANCE: The tongue is a muscular organ and plays a critical role in speech, deglutition, and taste. Tongue development defects severely affect the physiological function of the tongue. Despite these important functions of the tongue, we know very little about the control of tongue development. This research program is designed to obtain important information in order to have a clear understanding how different gene mutations adversely affect tissue-tissue interactions during tongue development and lead to tongue malformation. Ultimately, this investigation will provide important information on future prevention and treatment of skeletal muscle defects.